Pazopanib (Votrient) and sunitinib (Sutent) have been shown to provide progression-free survival benefit compared with placebo or interferon in phase III trials in metastatic renal cell carcinoma. In a noninferiority trial reported in The New England Journal of Medicine by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center, and colleagues, pazopanib was noninferior to sunitinib with regard to progression-free survival among patients with metastatic renal cell carcinoma.1 Moreover, the investigators reported that pazopanib was associated with better safety and quality-of-life profiles.
In this phase III open-label trial, 1,110 patients with clear-cell metastatic renal cell carcinoma from sites in 14 countries in North America, Europe, Australia, and Asia were randomly assigned to receive continuous dosing of pazopanib at 800 mg once daily (n = 557) or sunitinib in 6-week cycles of 50 mg once daily for 4 weeks followed by 2 weeks without treatment (n = 553 patients). The primary endpoint was progression-free survival, with the study being powered to show the noninferiority of pazopanib vs sunitinib.
The study protocol was amended to increase the patient sample size to 1,100 patients after it became clear that the original planned enrollment (876 patients) would be insufficient to observe the necessary number of disease progression events. Instead of reopening enrollment in the original trial, targeted enrollment was achieved by prospectively combining the sample in the original trial (927 patients) with the sample in an ongoing trial (183 patients), a substudy of the original trial conducted in China, Taiwan, and South Korea. The trials were identical in terms of patient selection criteria and design, except that health-related quality of life and medical resource utilization were not assessed in the substudy.
The pazopanib and sunitinib groups were well balanced for age (median, 61 and 62 years), region (eg, North America for 35% and 34%, Asia for 34% and 32%), prior nephrectomy (82% and 84%), prior radiation therapy (8% in both), Karnofsky performance status (90–100 in 75% and 76%), lactate dehydrogenase ≤ 1.5 times upper limit of normal (93% and 95%), number of involved organs (≥ 3 in 42% and 44%), most common metastatic sites (eg, lung in 76% and 77%, lymph nodes in 40% and 45%), Memorial Sloan-Kettering Cancer Center risk category (favorable in 27% in both, intermediate in 58% and 59%), and Heng risk category (favorable in 25% in both, intermediate in 54% and 56%).
Median duration of treatment was 8.0 months in the pazopanib group and 7.6 months in the sunitinib group. Median progression-free survival was 8.4 months (95% confidence interval [CI] = 8.3–10.9 months) in the pazopanib group and 9.5 months (95% CI = 8.3–11.1 months) in the sunitinib group. The hazard ratio (HR) for pazopanib vs sunitinib was 1.05 (95% CI = 0.90–1.22), which met the predefined criterion for noninferiority.
Subgroup analyses indicated that the results were not driven by any particular subgroup. Similar results were observed across ethnic groups and geographic regions. The post hoc hazard ratios for progression-free survival for pazopanib vs sunitinib were 1.06 (95% CI = 0.90–1.24) in the original study and 0.95 (95% CI = 0.60–1.48) in the substudy.
Response Rate and Overall Survival
The objective response rate was 31% in the pazopanib group (including one complete response) vs 25% in the sunitinib group (including three complete responses; P = .03). Median overall survival was 28.4 months (95% CI = 26.2–35.6 months) in the pazopanib group and 29.3 months (95% CI = 25.3–32.5 months) in the sunitinib group (HR = 0.91, P = .28 on stratified log-rank test).
Common adverse events of any grade that occurred in > 10% of patients in either group and that were reported significantly more frequently with sunitinib included hand-foot syndrome, mucosal inflammation, stomatitis, hypothyroidism, dysgeusia, dyspepsia, epistaxis, and fatigue. Those reported significantly more frequently with pazopanib included changes in hair color, weight loss, and alopecia.
Sunitinib patients had a significantly higher risk of grade 3 or 4 fatigue (18% vs 11%) and hand-foot syndrome (12% vs 6%) and higher risk of hematologic laboratory abnormalities of any grade and of grades 3 and 4, including grade 3 or 4 leukopenia (6% vs 1%), thrombocytopenia (22% vs 4%), neutropenia (20% vs 5%), and anemia (7% vs 2%). Pazopanib patients had significantly higher risk of increased levels of ALT or bilirubin and hypoglycemia of any grade and higher risk of grade 3 or 4 increases in ALT (17% vs 5%), AST (12% vs 3%), and alkaline phosphatase (3% vs 1%).
Cardiac dysfunction criteria were met by 13% of pazopanib patients and 11% of sunitinib patients, and the incidence of myocardial infarction or ischemia was 2% and 4%. Drug-related fatal adverse events occurred in 1% of both groups.
Dose interruption for at least 7 days occurred in 44% of pazopanib patients and 49% of sunitinib patients, dose reduction occurred in 44% and 51%, and discontinuation of study drug occurred in 24% and 20%, with the higher rate in the pazopanib group being primarily due to liver function test abnormalities (6% vs 1%).
Medical Resource Utilization
Pazopanib patients had significantly fewer monthly telephone consultations (P = .04) and emergency department visits (P = .003). In addition, pazopanib recipients had nonsignificantly fewer medical visits unrelated to the study and hospital days per month.
Quality of Life
During the first 6 months of treatment, the pazopanib group had significantly better outcomes on 11 of 14 quality-of-life measures, including the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale (P < .001); the Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) scales for treatment side effects (P = .03), disease-related physical symptoms (P = .03), and total score (P = .02); the Cancer Therapy Satisfaction Questionnaire scores for feelings about side effects (P < .001) and satisfaction with therapy (P < .001); and the Supplementary Quality of Life Questionnaire scores for worst mouth or throat soreness (P < .001), worst hand soreness (P = .002), worst foot soreness (P = .001), limitations due to mouth or throat soreness (P < .001), and limitations due to foot soreness (P = .01). Effect sizes were of a magnitude conventionally considered small to medium (0.20–0.50) for seven of these differences, small (< 0.20) for 3, and medium to large (0.50–0.80) for the difference in mouth and throat soreness.
The investigators concluded: “Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib…. Our study showed lower monthly use of medical resources with pazopanib than with sunitinib. These end points, plus health-related quality of life and the safety profile, assume special importance in comparative-effectiveness research when clinically similar (noninferior) treatments are being considered.” ■
Disclosure: The study was funded by GlaxoSmithKline Pharmaceuticals. For full disclosures of the study authors, visit www.nejm.org.
1. Motzer RJ, Hutson TE, Cella D, et al: Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369:722-731, 2013.